OBJECTIVES: The nitrosourea antitumor agents have demonstrated significant antitumor activity against a wide range of human malignancies. All members of this class of agents except streptozotocin produce severe bone marrow toxicity that often limits therapy. The objectives of this research include: 1. An understanding of the aqueous activation and pharmacologic action of nitrosourea anticancer agents to identify the principal metabolites responsible for anticancer activity, the delayed bone marrow toxicity, and explain the apparent specificity of the glucose carrier in reducing the myelosuppressive action. The studies will incorporate measurements of alkylation, carbamoylation, and chemical half life of established and recently synthesized nitrosourea antitumor agents. 2. The identification and development of new active nitrosourea anticancer agents which lack bone marrow toxicity. APPROACH: The comparative myelosuppression of available and newly synthesized agents will be compared after in vivo administration to normal and leukemic mice and in in vitro cultures of normal mouse and human bone marrow. These studies will incorporate measurements of DNA, RNA and protein synthesis, and colony-forming units. Correlations between relative in vitro and in vivo aklylating and carbamoylating active, myelosuppressive, and antitumor activity will be made in an attempt to develop structure-activity relationships for future drug synthesis. New active and non-myelosuppressive agents will be presented to the National Cancer Institute as candidate drugs for use in man.